Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

Dessaud, Éric; Yang, Lin; Hill, Katy; Cox, Barny; Ulloa, Fausto; Ribeiro, Ana; Mynett, Anita; Novitch, Bennett G.; Briscoe, James

doi:10.1038/nature06347

Cited by 560 publications

(677 citation statements)

References 33 publications

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“…It is possible that ptc1 could diffuse into ECM if it is processed in this compartment to be used as an inhibitor, as, for example, has been described for endoglin. Indeed, ptc1 has been reported to sequester hedgehog ligand and restrict its movement to generate hedgehog morphogen gradients (Dessaud et al 2007). These data suggest possible roles for SULFs in controlling Hedgehog signalling and unique functional roles for secreted SULF2 in the ECM.…”

Section: Discussionmentioning

confidence: 94%

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing

Zaman

Staines

Farquharson

et al. 2015

Histochem Cell Biol

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Highlights: High Sulf1/Sulf2 expression in active osteoblasts with reduction in osteocytes. High variability in Sulf1/Sulf2 expression in articular chondrocytes. Hypertrophic chondrocytes in growing and healing bone express high levels of Sulf2 but not Sulf1. High Sulf2 expression in growing and healing bone closely correlates with Hedgehog signalling.ABSTRACT: SULF1/SULF2 enzymes regulate cell signalling that impacts the growth and differentiation of many tissues. To determine their possible role in cartilage and bone growth or repair, their expression was examined during development and bone fracture healing using RT-PCR and immunochemical analyses. Examination of epiphyseal growth plates revealed differential, inverse patterns of SULF1 and SULF2 expression, with the former enriched in quiescent and the latter in hypertrophic chondrocyte zones. Markedly higher levels of both SULFs, however, were expressed in osteoblasts actively forming bone when compared with proliferating pre-osteoblasts in the periosteum or the entombed osteocytes which express the lowest levels. The increased Sulf1 and Sulf2 expression in differentiating osteoblasts was further confirmed by RT PCR analysis of mRNA levels in rat calvarial osteoblast cultures.SULF1 and SULF2 were expressed in most fetal articular chondrocytes but downregulated in a larger subset of cells in the postnatal articular cartilage. Unlike adult articular chondrocytes, SULF1/SULF2 expression varied markedly in postnatal hypertrophic chondrocytes in the growth plate, with very high SULF2 expression compared with SULF1 apparent during neonatal growth in both primary and secondary centres of ossification. Similarly, hypertrophic chondrocytes expressed greatly higher levels of SULF2 but not SULF1 during bone fracture healing. SULF2 expression unlike SULF1 also spread to the calcifying matrix around the hypertrophic chondrocytes indicating its possible ligand inhibiting role through HSPG desulfation. Higher levels of SULF2 in both developing and healing bone closely correlated with parallel increases in hedgehog signalling analysed by ptc1 receptor expression.

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Section: Discussionmentioning

confidence: 94%

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing

Zaman

Staines

Farquharson

et al. 2015

Histochem Cell Biol

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“…Graph shows mean ± SEM PKA activity (P-substrate/non-P-substrate optical density ratio) for the indicated treatments; n ≥ 5, *P < 0.05, **P < 0.001, ***P < 5E- resolution and ensure effective down-regulation of the canonical Shh signaling as spinal cord development progresses. It is known that the Shh receptor Patched acts as a negative feedback regulator of canonical signaling, assuring precise patterning of spinal neural progenitors (4,5). However, such a regulatory mechanism predicts temporal adaptation of cells to Shh (4,5) rather than switching off of canonical signaling.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that the Shh receptor Patched acts as a negative feedback regulator of canonical signaling, assuring precise patterning of spinal neural progenitors (4,5). However, such a regulatory mechanism predicts temporal adaptation of cells to Shh (4,5) rather than switching off of canonical signaling. The long-term down-regulation of canonical Shh signaling may have important implications.…”

Section: Discussionmentioning

confidence: 99%

“…During the early stages of spinal cord development, Shh is synthesized and secreted by the notochord and floor plate to form a ventrodorsal concentration gradient, imprinting a spatiotemporal profile of Gli activity (4,5) that specifies neural progenitors (6)(7)(8)(9). Despite persistence of Shh gradient and increased Shh levels as spinal cord development progresses (3,10), Gli activity is switched off (3,4) by unknown mechanisms.…”

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confidence: 99%

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Inversion of Sonic hedgehog action on its canonical pathway by electrical activity

Belgacem

Borodinsky

2015

Proc. Natl. Acad. Sci. U.S.A.

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Sonic hedgehog (Shh) is a morphogenic protein that operates through the Gli transcription factor-dependent canonical pathway to orchestrate normal development of many tissues. Because aberrant levels of Gli activity lead to a wide spectrum of diseases ranging from neurodevelopmental defects to cancer, understanding the regulatory mechanisms of Shh canonical pathway is paramount. During early stages of spinal cord development, Shh specifies neural progenitors through the canonical signaling. Despite persistence of Shh as spinal cord development progresses, Gli activity is switched off by unknown mechanisms. In this study we find that Shh inverts its action on Gli during development. Strikingly, Shh decreases Gli signaling in the embryonic spinal cord by an electrical activity- and cAMP-dependent protein kinase-mediated pathway. The inhibition of Gli activity by Shh operates at multiple levels. Shh promotes cytosolic over nuclear localization of Gli2, induces Gli2 and Gli3 processing into repressor forms, and activates cAMP-responsive element binding protein that in turn represses gli1 transcription. The regulatory mechanisms identified in this study likely operate with different spatiotemporal resolution and ensure effective down-regulation of the canonical Shh signaling as spinal cord development progresses. The developmentally regulated intercalation of electrical activity in the Shh pathway may represent a paradigm for switching from canonical to noncanonical roles of developmental cues during neuronal differentiation and maturation.

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“…The floorplate, as demarcated by the highest levels of FOXA2 and SHH synthesis, extends to the dorsal limits of the latter, but only to mid-regions of the neural tube in the former. This may reflect the importance of timing in HHdependent patterning (Balaskas et al, 2012;Dessaud et al, 2008;Dessaud et al, 2007). In Ptch1 −/− embryos, ectopic signaling occurs once cells gain competence to initiate a HH response.…”

Section: Discussionmentioning

confidence: 99%

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

et al. 2013

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SUMMARYHedgehog (HH) signaling is essential for vertebrate and invertebrate embryogenesis. In Drosophila, feedback upregulation of the HH receptor Patched (PTC; PTCH in vertebrates), is required to restrict HH signaling during development. By contrast, PTCH1 upregulation is dispensable for early HH-dependent patterning in mice. Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2. Although HHIP1 functions semi-redundantly with PTCH1 to restrict HH signaling in the developing nervous system, a role for PTCH2 remains unresolved. Data presented here define a novel role for PTCH2 as a ciliary localized HH pathway antagonist. While PTCH2 is dispensable for normal ventral neural patterning, combined removal of PTCH2-and PTCH1-feedback antagonism produces a significant expansion of HH-dependent ventral neural progenitors. Strikingly, complete loss of PTCH2-, HHIP1-and PTCH1-feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation. Overall, these data reveal an essential role for liganddependent feedback inhibition of vertebrate HH signaling governed collectively by PTCH1, PTCH2 and HHIP1.

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Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism

Cited by 560 publications

References 33 publications

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing

Inversion of Sonic hedgehog action on its canonical pathway by electrical activity

Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning

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